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* Residue conservation analysis
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DOI no:
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J Biol Chem
278:27981-27987
(2003)
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PubMed id:
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Structural basis for the specificity of bipartite nuclear localization sequence binding by importin-alpha.
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M.R.Fontes,
T.Teh,
D.Jans,
R.I.Brinkworth,
B.Kobe.
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ABSTRACT
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Importin-alpha is the nuclear import receptor that recognizes cargo proteins
carrying conventional basic monopartite and bipartite nuclear localization
sequences (NLSs) and facilitates their transport into the nucleus. Bipartite
NLSs contain two clusters of basic residues, connected by linkers of variable
lengths. To determine the structural basis of the recognition of diverse
bipartite NLSs by mammalian importin-alpha, we co-crystallized a
non-autoinhibited mouse receptor protein with peptides corresponding to the NLSs
from human retinoblastoma protein and Xenopus laevis phosphoprotein N1N2,
containing diverse sequences and lengths of the linker. We show that the basic
clusters interact analogously in both NLSs, but the linker sequences adopt
different conformations, whereas both make specific contacts with the receptor.
The available data allow us to draw general conclusions about the specificity of
NLS binding by importin-alpha and facilitate an improved definition of the
consensus sequence of a conventional basic/bipartite NLS (KRX10-12KRRK) that can
be used to identify novel nuclear proteins.
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Selected figure(s)
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Figure 2.
FIG. 2. Structures of complexes. A, structure of RB
peptide-m-Imp  complex. m-Imp is shown
as a ribbon diagram (yellow; drawn with the program RIBBONS
(40)). The superhelical axis of the repetitive part of the
molecule is approximately horizontal. The NLS peptide is shown
in a ball-and-stick representation, colored blue. B, structure
of N1N2 peptide-m-Imp complex, shown as in A.
The bound peptide is colored red.
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Figure 3.
FIG. 3. Peptide-importin- interaction. A,
schematic diagram of the interactions between the RB peptide and
m-Imp . Polar contacts are
shown with dashed lines, and hydrophobic contacts are indicated
by arcs with radiating spokes. The NLS peptide residues are
labeled with R. The water molecules are labeled with S. Carbon,
nitrogen, and oxygen atoms are shown in black, white, and gray,
respectively. This figure was prepared with the program LIGPLOT
(41). B, schematic diagram of the interactions between the N1N2
peptide and m-Imp , shown as in A. The
NLS peptide residues are labeled with N.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
27981-27987)
copyright 2003.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.M.Mehdi,
M.S.Sehgal,
B.Kobe,
T.L.Bailey,
and
M.Bodén
(2011).
A probabilistic model of nuclear import of proteins.
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Bioinformatics,
27,
1239-1246.
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F.Iwamoto,
T.Umemoto,
K.Motojima,
and
Y.Fujiki
(2011).
Nuclear transport of peroxisome-proliferator activated receptor α.
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J Biochem,
149,
311-319.
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R.Webel,
J.Milbradt,
S.Auerochs,
V.Schregel,
C.Held,
K.Nöbauer,
E.Razzazi-Fazeli,
C.Jardin,
T.Wittenberg,
H.Sticht,
and
M.Marschall
(2011).
Two isoforms of the protein kinase pUL97 of human cytomegalovirus are differentially regulated in their nuclear translocation.
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J Gen Virol,
92,
638-649.
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A.Giesecke,
and
M.Stewart
(2010).
Novel binding of the mitotic regulator TPX2 (target protein for Xenopus kinesin-like protein 2) to importin-alpha.
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J Biol Chem,
285,
17628-17635.
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PDB code:
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A.Lange,
L.M.McLane,
R.E.Mills,
S.E.Devine,
and
A.H.Corbett
(2010).
Expanding the definition of the classical bipartite nuclear localization signal.
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Traffic,
11,
311-323.
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D.Liu,
X.Wu,
M.D.Summers,
A.Lee,
K.J.Ryan,
and
S.C.Braunagel
(2010).
Truncated isoforms of Kap60 facilitate trafficking of Heh2 to the nuclear envelope.
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Traffic,
11,
1506-1518.
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G.Merényi,
E.Kónya,
and
B.G.Vértessy
(2010).
Drosophila proteins involved in metabolism of uracil-DNA possess different types of nuclear localization signals.
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FEBS J,
277,
2142-2156.
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J.B.Kelley,
A.M.Talley,
A.Spencer,
D.Gioeli,
and
B.M.Paschal
(2010).
Karyopherin alpha7 (KPNA7), a divergent member of the importin alpha family of nuclear import receptors.
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BMC Cell Biol,
11,
63.
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K.Das,
J.M.Aramini,
L.C.Ma,
R.M.Krug,
and
E.Arnold
(2010).
Structures of influenza A proteins and insights into antiviral drug targets.
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Nat Struct Mol Biol,
17,
530-538.
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R.Pawłowski,
E.K.Rajakylä,
M.K.Vartiainen,
and
R.Treisman
(2010).
An actin-regulated importin α/β-dependent extended bipartite NLS directs nuclear import of MRTF-A.
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EMBO J,
29,
3448-3458.
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D.A.Mason,
D.E.Stage,
and
D.S.Goldfarb
(2009).
Evolution of the metazoan-specific importin alpha gene family.
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J Mol Evol,
68,
351-365.
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K.E.Süel,
and
Y.M.Chook
(2009).
Kap104p imports the PY-NLS-containing transcription factor Tfg2p into the nucleus.
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J Biol Chem,
284,
15416-15424.
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L.M.McLane,
and
A.H.Corbett
(2009).
Nuclear localization signals and human disease.
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IUBMB Life,
61,
697-706.
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S.M.Dias,
K.F.Wilson,
K.S.Rojas,
A.L.Ambrosio,
and
R.A.Cerione
(2009).
The molecular basis for the regulation of the cap-binding complex by the importins.
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Nat Struct Mol Biol,
16,
930-937.
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PDB codes:
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G.Pontarin,
A.Fijolek,
P.Pizzo,
P.Ferraro,
C.Rampazzo,
T.Pozzan,
L.Thelander,
P.A.Reichard,
and
V.Bianchi
(2008).
Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage.
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Proc Natl Acad Sci U S A,
105,
17801-17806.
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K.E.Süel,
H.Gu,
and
Y.M.Chook
(2008).
Modular organization and combinatorial energetics of proline-tyrosine nuclear localization signals.
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PLoS Biol,
6,
e137.
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M.Hatayama,
T.Tomizawa,
K.Sakai-Kato,
P.Bouvagnet,
S.Kose,
N.Imamoto,
S.Yokoyama,
N.Utsunomiya-Tate,
K.Mikoshiba,
T.Kigawa,
and
J.Aruga
(2008).
Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain.
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Hum Mol Genet,
17,
3459-3473.
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PDB code:
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A.Glassmann,
S.Molly,
L.Surchev,
T.A.Nazwar,
M.Holst,
W.Hartmann,
S.L.Baader,
J.Oberdick,
T.Pietsch,
and
K.Schilling
(2007).
Developmental expression and differentiation-related neuron-specific splicing of metastasis suppressor 1 (Mtss1) in normal and transformed cerebellar cells.
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BMC Dev Biol,
7,
111.
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F.Tarendeau,
J.Boudet,
D.Guilligay,
P.J.Mas,
C.M.Bougault,
S.Boulo,
F.Baudin,
R.W.Ruigrok,
N.Daigle,
J.Ellenberg,
S.Cusack,
J.P.Simorre,
and
D.J.Hart
(2007).
Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit.
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Nat Struct Mol Biol,
14,
229-233.
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PDB codes:
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K.E.Stevens,
and
R.S.Mann
(2007).
A balance between two nuclear localization sequences and a nuclear export sequence governs extradenticle subcellular localization.
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Genetics,
175,
1625-1636.
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K.J.Bradley,
M.R.Bowl,
S.E.Williams,
B.N.Ahmad,
C.J.Partridge,
A.L.Patmanidi,
A.M.Kennedy,
N.Y.Loh,
and
R.V.Thakker
(2007).
Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal.
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Oncogene,
26,
1213-1221.
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M.J.Pryor,
S.M.Rawlinson,
R.E.Butcher,
C.L.Barton,
T.A.Waterhouse,
S.G.Vasudevan,
P.G.Bardin,
P.J.Wright,
D.A.Jans,
and
A.D.Davidson
(2007).
Nuclear localization of dengue virus nonstructural protein 5 through its importin alpha/beta-recognized nuclear localization sequences is integral to viral infection.
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Traffic,
8,
795-807.
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S.M.Stinnett,
E.A.Espeso,
L.Cobeño,
L.Araújo-Bazán,
and
A.M.Calvo
(2007).
Aspergillus nidulans VeA subcellular localization is dependent on the importin alpha carrier and on light.
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Mol Microbiol,
63,
242-255.
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A.S.Madrid,
and
K.Weis
(2006).
Nuclear transport is becoming crystal clear.
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Chromosoma,
115,
98.
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B.Friedrich,
C.Quensel,
T.Sommer,
E.Hartmann,
and
M.Köhler
(2006).
Nuclear localization signal and protein context both mediate importin alpha specificity of nuclear import substrates.
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Mol Cell Biol,
26,
8697-8709.
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E.Alvarez,
W.Zhou,
S.E.Witta,
and
C.R.Freed
(2005).
Characterization of the Bex gene family in humans, mice, and rats.
|
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Gene,
357,
18-28.
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L.F.Pemberton,
and
B.M.Paschal
(2005).
Mechanisms of receptor-mediated nuclear import and nuclear export.
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Traffic,
6,
187-198.
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D.S.Goldfarb,
A.H.Corbett,
D.A.Mason,
M.T.Harreman,
and
S.A.Adam
(2004).
Importin alpha: a multipurpose nuclear-transport receptor.
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Trends Cell Biol,
14,
505-514.
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H.M.Johnson,
P.S.Subramaniam,
S.Olsnes,
and
D.A.Jans
(2004).
Trafficking and signaling pathways of nuclear localizing protein ligands and their receptors.
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Bioessays,
26,
993.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
